Ketamine for bipolar depression: an updated systematic review

Background: The therapeutic potential of subanesthetic doses of ketamine appears promising in unipolar depression; however, its effectiveness in treating bipolar depression (BD) remains uncertain. Objective: This systematic review aimed to summarize findings on the use of ketamine for the treatment of BD by assessing its efficacy, safety, and tolerability. Design: Systematic review. Methods: We conducted a systematic review of studies that investigated the use of ketamine for adults with BD. We searched PubMed and Embase for relevant randomized-controlled trials, open-label trials, and retrospective chart analyses published from inception to 13 March 2023. Results: Eight studies were identified [pooled n = 235; mean (SD) age: 45.55 (5.54)]. All participants who received intravenous (IV) ketamine were administered a dose of 0.5–0.75 mg/kg as an adjunctive treatment to a mood-stabilizing agent, whereas participants who received esketamine were administered a dosage ranging from 28 to 84 mg. Flexible dosing was used in real-world analyses. A total of 48% of participants receiving ketamine achieved a response (defined as ⩾50% reduction in baseline depression severity), whereas only 5% achieved a response with a placebo. Real-world studies demonstrated lower rates of response (30%) compared to the average across clinical trials (63%). Reductions in suicidal ideation were noted in some studies, although not all findings were statistically significant. Ketamine and esketamine were well tolerated in most participants; however, six participants (2% of the overall sample pool, 5 receiving ketamine) developed hypomanic/manic symptoms after infusions. Significant dissociative symptoms were observed at the 40-min mark in some trials. Conclusion: Preliminary evidence suggests IV ketamine as being safe and effective for the treatment of BD. Future studies should focus on investigating the effects of repeated acute and maintenance infusions using a randomized study design.


Introduction
5][6] While there is a clear consensus for the definition of treatment-resistant depression (TRD), the same does not apply to the definition of TRBD, for which there are various consensus definitions. 7Although BD is of significant concern, there are currently only five Food and Drug Administration (FDA)approved treatment options available. 8Although TherapeuTic advances in psychopharmacology some trials have suggested the effectiveness of electroconvulsive therapy and repetitive transcranial magnetic stimulation for BD, 9,10 more research is needed to arrive at conclusive results.2][13] While pharmacotherapy (e.g.conventional mood stabilizers and antipsychotics) is the primary treatment option for BD, there are significant challenges and limitations such as treatment resistance, relapse, and several adverse side effects including metabolic issues and cognitive impairments. 2,4,14Therefore, there is a pressing demand for novel therapeutic options for BD with a focus on interventions offering improved antidepressant and anti-suicidal efficacy while minimizing adverse side effects and consideration for treatment-emergent mania. 4,8,15,16tamine is a dissociative anesthetic originally developed as an anesthetic agent; however, recent evidence additionally highlights its rapid-acting antidepressant effects at sub-anesthetic doses (e.g.0.5-1.0mg/kg infused over 40-60 min). 8,17,18etamine's mechanism of action primarily involves modulation of the glutamatergic system, rather than the monoamine systems typically targeted by conventional antidepressants. 19,20oreover, its mechanism of action goes beyond simple N-methyl-D-aspartate antagonism itself, involving multiple other mechanisms (involving brain-derived neurotrophic factor, glycogen synthase kinase-3 beta, and membrane ionic influx). 21][24] However, the majority of randomized controlled trials (RCTs) examining ketamine have been limited to single-dose proof-of-concept studies looking at the adult TRD population. 4[27][28] As outlined in recent reviews, RCT findings primarily support the effectiveness of IV ketamine in MDD, but it remains unclear whether the same holds true for BD. 1,23,29Furthermore, the generalizability of these findings in the real-world setting remains uncertain given the increased complexity and comorbidity observed in the TRBD population. 4Despite previous reviews examining the potential of ketamine as a treatment for TRBD, 30 recent advancements in ketamine research necessitate an updated evaluation of its therapeutic value through RCTs and real-world effectiveness (RWE) data.The importance of RWE data has been increasingly emphasized and recognized as an essential companion to RCTs, as it provides a more comprehensive understanding of the practical implications of using ketamine for BD. 31 For the current invited review, our goal is to present an updated summary of the research on the efficacy and safety of ketamine in treating BD.A systematic review that synthesizes findings from RCTs, open-label studies, and RWE data will be conducted.

Protocol and registration
This study was recorded on the Open Science Framework (https://osf.io/ksvnb/)and adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews. 32

Eligibility criteria
Our inclusion criterion was restricted to studies that investigated the use of ketamine in any form in adults (18 years and older) for the treatment of BD.RCTs, open-label trials, retrospective chart analyses, and RWE studies that evaluated the use of ketamine as a stand-alone treatment or in conjunction with psychotherapy were considered.Research designs involving surveys, cohort studies, case series, reviews, post hoc/secondary analyses, commentaries, and clinical overviews were excluded.In addition, studies needed to report at least one outcome related to the efficacy or safety of ketamine (e.g.response to treatment or adverse events).Finally, studies failing to differentiate between unipolar and BD were also excluded. of these databases to 13 March 2023, using the following medical search heading (MeSH) terms and search strings: [[[(ketamine) OR (esketamine)] OR (arketamine)] OR (racemic ketamine)] AND (bipolar depression).To identify any ongoing or unpublished studies, we also searched ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry using the keywords 'ketamine' and 'bipolar depression'.In addition, we manually searched the reference lists of the included studies and relevant reviews to find potentially applicable articles.

Study selection
Using the web-based systematic review tool Covidence (Veritas Health Innovation), two researchers (FF and SH) individually reviewed titles and abstracts to identify relevant articles.The co-authors independently evaluated the full texts of the selected articles for inclusion.In the event of any discrepancies, they engaged in a discussion to reconcile their differences and come to a consensus.

Data collection process and data items
Using a custom data extraction template in Microsoft Excel that captured patient demographics, response and remission rates, and adverse events, three co-authors (FF, SH, and DC) gathered information on various aspects of the studies including interventions, study outcomes, ketamine dosage, study withdrawals, and adverse events.

Risk of bias in individual studies
To evaluate the potential for bias within each trial, we utilized the Cochrane risk of bias tool for RCTs.This tool evaluates various factors, including selection bias, performance bias, detection bias, attrition bias, and reporting bias. 33Two authors (DC and DJ) independently conducted the risk of bias assessments.In case of any discrepancies between the two authors, they discussed to come to a consensus.

Study selection
Using the outlined search strategy, a total of 2160 records were identified (Figure 1).After duplicates were removed, 1445 records remained.A title and abstract screening was done on these records, leaving 47 records for a full-text review.Eight studies met the inclusion criteria and were ultimately included in our analysis.

Characteristics of studies, participants, and interventions
Table 1 shows the characteristics of the studies included in this analysis.Three studies were RCTs, 24,34,35 three were open-label, singlearm, [36][37][38] one study was an open-label, doublearm, real-world observational trial, 39 and one was a real-world observational trial. 4Four studies 34,35,38,40 included single ketamine infusions, whereas three studies 4,36,37 included multiple infusions.Seven studies 4,[34][35][36][37][38]40 used racemic intravenous ketamine as the intervention, whereas one study used an esketamine nasal spray. 39A total of 235 participants were included [mean (SD) age: 45.5 (5.53); 60.9% female].With the exception of one study, 35 all participants had Diagnostic and Statistical Manual of Mental Disorder IV-or 5-diagnosed BD that failed to respond to one or more complete trials of mood stabilizing medications. Silinical trial studies used racemic ketamine at a dose of 0.5 mg/kg delivered intravenously with an adjunctive mood stabilizer that was used throughout ketamine treatment.[34][35][36][37][38]40 In the RWE trial, participants had the potential to receive a maximum dose of 0.75 mg/kg if sufficient response was not achieved after the first two doses.4 In the two-arm observational trial 39 of patients with TRBD and TRD (the latter of which is excluded from this review), participants received a variable number of esketamine doses at a dosage of 28-84 mg (see Table 4 in Martinotti and colleagues' report).The nasal spray formulation for the Italian esketamine study (ESK-NS) consisted of two doses of intranasal esketamine administered per week in the first month, and one dose per week in the following 2 months (28-84 mg).39 All racemic ketamine trials excluded participants who had psychotic symptoms or a history of substance abuse, and most studies excluded those who had comorbid general medical conditions or who were pregnant or breastfeeding.In the esketamine trial, 39 patients with comorbid physical conditions that are contraindicated to esketamine treatment were excluded (Tables 2 and 3).

Efficacy of IV ketamine in clinical trials
The overall pooled response rate (defined as those having a reduction in their baseline depression severity of at least 50%) across all eight studies was 48% for those receiving ketamine (94/203).The range of response rates across studies varied from 26% 4 to 79%. 40For the three studies involving control groups, 24,34,35 the overall placebo-pooled response rate was 5% (2/42).The efficacy of single-dose ketamine did not extend beyond the 2-week mark; however, studies administering repeated infusions of ketamine over 2 weeks showed longer-lasting efficacy, up to and including a month after initial administration. 36rge reductions were found in suicidal symptoms after one or more infusions across all trials.However, the significance of these findings  varied.In an open-label trial, suicidal ideation was significantly reduced at 4 h post-infusion compared to baseline, with sustained reductions across multiple infusions. 36In one RCT, the change in suicidal ideation was not significantly different between the ketamine and midazolam groups. 35In the ketamine arm, 57% (4/7) of patients responded and 43% (3/7) were in  score) and 20% of patients met criteria for remission (QIDS-SR16 ⩽ 5). 4 Moreover, there was a trend toward greater depressive symptoms reduction in the BD-II group compared to BD-I.
Ketamine was also associated with improved anxiety scores and psychosocial functioning.
A significant effect of infusion for anxiolytic symptoms was observed, as measured by the General Anxiety Disorder 7-item (GAD-7) scale, F(2, 82.5) = 8.99, p < 0.001, Cohen's f = 0.43).Lastly, there was no significant main effect of In the real-world study of esketamine, 39 response and remission rates at 1 month were 25.7% and 17.14%, with those rates increasing to 68.57% and 48.57% at 2 months post-baseline, respectively.

Safety and tolerability of IV ketamine for BD
Across clinical trials, 24,34,35 participants tolerated IV ketamine treatment reasonably well.Common adverse events included perceptual and physical changes such as drowsiness, dizziness, blurred vision, nausea, and headaches, which resolved soon after the end of infusions.Transient increases in blood pressure and heart rate were also noted throughout the trials, which resolved after infusions.Some significant adverse events were noted.For example, two participants in the RCTs (one receiving ketamine and one receiving placebo) developed manic symptoms. 34One participant (2.85%) in the open-label, two-arm observational study experienced an affective switch. 39Participants in two trials also developed significant dissociative symptoms 34,40 ; however, this was not noted in other trials.With regard to RWE data, infusions were well tolerated with treatment-emergent hypomania observed in only 3/66 patients (4.5%) with zero cases of mania or psychosis. 4

Efficacy
To our knowledge, this systematic review is the latest to investigate the efficacy, safety, and tolerability of IV ketamine in treating BD.Based on the analysis of the eight included studies, our results suggest that IV ketamine is a promising, safe, and effective treatment option for BD and TRBD.The overall pooled response rate across all eight studies was 48% for those receiving ketamine (94/203).The overall range of response rates varied from 35% to 79% across the included studies.
The wide range of the overall response rate across studies can be attributed to several factors.One explanation for the wide range of response rates could be due to inherent variability in the levels of treatment resistance of participants across the different studies. 4The lower end of the overall response rate for RWE analysis is conservative and more realistic compared to the earlier studies reflecting the complex BD patient population. 40n the RWE analysis, study inclusion criteria were less strict, representing a more 'real-world' sample and the study also permitted a dose increase after the first two infusions, providing another avenue for the discrepancies. 4In addition, the small sample size of (n = 15) in prior trials may be another reason why results varied from the RWE study, which had a sample size of 66 participants.
The RWE analysis was the first study delineating between type I and type II BD and to our knowledge, this study represents the largest sample size of the well-characterized group of adults with TRBD receiving repeated ketamine infusions at a community-based clinic. 4A key finding in this delineation was a trend toward a higher reduction of depressive symptoms in the BD-II group compared to BD-I; nonetheless, more studies with larger sample sizes are needed to confirm this trend. 4Taken together, our results support prior findings indicating that IV ketamine infusions were associated with significant improvements in depressive symptoms in adults with BD.

Single versus repeated doses
There is currently limited data available on repeated administration of IV ketamine for BD.The evidence to date for the use of repeated ketamine infusions for BD is derived primarily from journals.sagepub.com/home/tpp

TherapeuTic advances in psychopharmacology
open-label studies with conflicting results. 4To this end, future RCT designs taking into consideration both acute and maintenance treatments are needed to further evaluate the long-term benefits and implications.

Suicidality
2][43] While reductions in suicidal symptoms after one or more infusions across trials varied in significance, it is important to note the downward trend across all studies.Lastly, no participants reported an increase in their preexisting suicidal thoughts following ketamine infusions.

Anxiety
In addition to its rapid anti-depressive and antisuicidal effects, ketamine also leads to improved anxiety symptoms as seen in Fancy and colleague's RWE analysis. 4They observed a significant fourpoint reduction from baseline to post-treatment assessment visit in GAD-7 scores suggesting a reduction from severe to moderate anxiety. 4While there are currently no studies specifically investigating the effects of repeated ketamine infusions on anxiety, our findings are consistent with other trials suggesting the potential of ketamine to alleviate anxiolytic symptoms. 3,6,42,44,45ychosocial functioning With respect to psychosocial functioning, a RWE study reported significant improvement in SDS 'social' and 'family' subdomains, but no improvements in the 'work' subdomain. 4One explanation for this may be that workplace functioning has a longer latency to improvement due to practical reasons (e.g.individuals needing time to find a job after recovery). 46][47] Overall, there is insufficient reporting in the current literature to draw conclusive findings on ketamine's effect on psychosocial functioning.Further investigation is warranted to explore the potential psychosocial and interpersonal benefits of ketamine infusions in patients with BD.

Safety and tolerability
While there is a growing body of research supporting the use of ketamine as an antidepressant for MDD, some researchers have been hesitant to include bipolar-depressed patients in these studies due to concerns about the risk of treatmentemergent affective switching and the risk of dissociation.Despite these concerns, this review demonstrates that recent research supports a relatively low risk of manic switching and dissociation with ketamine treatment.The majority of studies suggest that IV ketamine is a generally well-tolerated treatment for BD.
Of the studies included in this review, only two reported instances of treatment-emergent affective switching.One RCT included in this review reported that one participant receiving ketamine developed manic symptoms, 34 and a RWE study reported three cases of hypomania after the third or fourth ketamine infusion. 4[50] It is important to note that while the risk of manic switching with IV ketamine treatment is relatively low, it is still a potential risk that should be closely monitored and further characterized in future trials.Patients with BD who receive ketamine should be assessed post-infusion for signs of mood elevation with a well-validated tool for assessing mania, such as the Young Mania Rating Scale.
Only two trials reported participants developing significant dissociative symptoms, which typically occurred 40 min after receiving the ketamine infusion. 34,40Nevertheless, in the remaining four trials, there were no significant observations of dissociation or manic switch throughout the duration of the studies.While standard antidepressants can induce rapid cycling, it is uncertain whether ketamine can induce the same, as trials involving ketamine are usually brief.While there have been instances of manic switching in some participants who received a single ketamine infusion, the small sample sizes in these cases may be insufficiently powered to identify manic switching.However, one study involving 98 participants with MDD found insufficient evidence to support the induction of mania through a single sub-anesthetic dose of ketamine. 51spite the potential risk of manic switch and dissociation, adults with TRBD should be included in studies assessing the antidepressant effect of ketamine.BD is a debilitating condition that affects a significant portion of the population, and approximately one-third of patients will not experience syndromal relief with multiple first-line therapies, resulting in a diagnosis of TRBD.Thus, it is essential to investigate potential treatment options for patients who do not respond to standard treatments.

Limitations
Although there are some strengths to this review, it is important to note several fundamental limitations.First, publication bias may have influenced our findings, as studies showing no or minimal improvements from IV ketamine may have been overlooked.Second, although we made an effort to cover a significant follow-up period after ketamine treatment administration, we were unable to obtain comprehensive information beyond the 2-week mark.Therefore, our review's results are constrained to this timeframe.Third, the participants from which we drew data may not be representative of the broader population with BD because of strict inclusion/exclusion criteria.However, we included an RWE analysis to account for this.While Fancy and colleagues' RWE analysis 4 was the first to delineate between type I and type II BD, more RWE research is needed to complement RCT findings to achieve a more holistic understanding of ketamine's effectiveness.Fourth, it is worth noting that the significant heterogeneity within the included studies may have influenced our results.For instance, there are distinctions between patients with TRBD and those without, as well as differences between those who were treated as inpatients versus those treated at community clinics.Fifth, variations exist between studies in which participants received either a single ketamine dose or multiple doses.Sixth, seven of the eight studies used racemic ketamine while one study used the S-enantiomer of ketamine (ESK-NS).Data on the use of arketamine (R-enantiomer of ketamine) remain scarce with there being only one pilot trial to date testing its feasibility and safety for BD. 52Thus, there are literature limitations on the formulations of ketamine and its enantiomers and their respective impact on the safety and tolerability of observed outcomes.Lastly, the long-term efficacy, safety, and tolerability of maintenance ketamine infusions have not been fully studied.While promising preliminary evidence exists for the acute antidepressant effects of ketamine for BD, more research is needed to understand its long-term effects.

Future directions
It is an exciting time for ketamine research in depression, and the literature on ketamine in BD is catching up to the literature on MDD.RCTs evaluating the efficacy of repeated ketamine infusions are needed to determine whether the initial depressive benefits can be sustained, as single-dose ketamine seems to provide transient benefits.Similarly, the effects of maintenance ketamine infusions for long-term antidepressant benefits are required.In addition, the effects of combining ketamine with other non-pharmacotherapeutic treatment options should be explored.Table 4 displays current registered clinical trials investigating the use of ketamine for BD.

Conclusion
Ketamine is an experimental, innovative treatment for BD with rapid action.This systematic review supports the use of IV racemic ketamine for individuals with BD, based on preliminary evidence.Although several clinical studies have demonstrated significant short-term benefits, the long-term benefits remain inadequately explored.Although ketamine is not currently approved by the FDA for any mental disorder, its isomer, esketamine, is the first FDA-approved non-monoamine-based psychotropic agent for adults with TRD.Nevertheless, ketamine is recommended for MDD as a treatment option when two prior antidepressants are insufficient (i.e.treatment-resistant).More RCTs, as well as RWE data, are necessary to explore the efficacy and safety of administering IV ketamine for treating BD.

Figure 1 .
Figure 1.Preferred Reporting Items for Systematic Reviews and Meta-analyses flow diagram outlining the systematic review.

Table 1 .
Characteristics of studies included.

Table 2 .
Risk of bias assessment for included RCTs as per Cochrane's risk of bias tool.

Table 3 .
Risk of bias assessment for included open-label studies as per Cochrane's risk of bias in non-randomized studies -of interventions tool.

Table 4 .
Ongoing clinical trials of ketamine for bipolar depression.